Ebook Embryology at a glance: Part 2

(BQ) Part 2 book Embryology at a glance presents the following contents: Skeletal system (ossification), skeletal system, muscular system, respiratory system, digestive system - Gastrointestinal tract, urinary system, endocrine system, central nervous system, peripheral nervous system,...

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 21.1

Mesenchymal cells condense

and form a model of the future bone

Figure 21.4

The diaphysis becomes ossified but the epiphyses

remain cartilaginous

Figure 21.6

With the epiphyses and diaphysis ossified, the bone

continues to grow in length from the growth plates

Eventually the growth plates also ossify, and growth ceases

Figure 21.5

Later, the epiphyses also begin to ossify

Figure 21.7Mesenchymal cells form a condensation between 2 developing bones

Figure 21.8Mesenchymal cells become organised into layers, and differentiateinto different cell types, in this case the tissues of a synovial joint

Figure 21.2Mesenchymal cells differentiate into chondrocytes, and the matrix becomescalcified in the future diaphysis

Figure 21.3Blood vessels invade, bringing progenitor cells thatbecome osteoblasts and haematopoietic cells

HypertrophicchondrocytesPerichondrium Periosteum, bone

forming beneath

Osteoblasts Primary centre of

ossification

EpiphysisDiaphysis

Bony spicules

Secondarycentre ofossification

Epiphyseal growth plate

Stages of endochondral ossification

Bone (epiphysis)

Joint capsule

Articular cartilage

Internal ligamentSynovial membrane

Joint development

Skeletal system: ossification Systems development 51

Time period: week 5 to adult

Introduction

Mesodermal cells form most bones and cartilage Initially an

embryonic, loosely organised connective tissue forms from meso­

derm throughout the embryo, referred to as mesenchyme Neural

crest cells that migrate into the pharyngeal arches are also involved

in the development of bones and other connective tissues in the

head and neck (see Chapters 39–42)

Bones begin to form in one of two ways A collection of mesen­

chymal cells may group together and become tightly packed (con­

densed), forming a template for a future bone This is the start of

endochondral ossification (Figure 21.1) Alternatively, an area of

mesenchyme may form a hollow sleeve roughly in the shape of the

future bone This is how intramembranous ossification begins

Long bones form by endochondral ossification (e.g femur,

phalanges) and flat bones form by intramembranous ossification

(e.g parietal bones, mandible)

Endochondral ossification

The cells of the early mesenchymal model of the future bone dif­

ferentiate to become cartilage (chondrocytes) This cartilage model

then begins to ossify from within the diaphysis (the shaft of the

long bone) This is the primary centre of ossification, and the

chondrocytes here enter hypertrophy (Figure 21.2) As they

become larger they enable calcification of the surrounding extra­

cellular matrix, and then die by apoptosis

The layer of perichondrium that surrounded the cartilage model

becomes periosteum as the cells here differentiate into osteoblasts,

and bone is formed around the edge of the diaphysis This will

become the cortical (compact) bone (Figures 21.2 and 21.3)

Blood vessels invade the diaphysis and bring progenitor cells

that will form osteoblasts and haematopoietic cells of the future

bone marrow (Figure 21.3) Bone matrix is deposited by the oste­

oblasts on to the calcified cartilage, and bone formation extends

outwards to either end of the long bone (Figure 21.4) Osteoclasts

also appear, resorbing and remodelling the new bony spicules of

spongy (trabecular) bone

When osteoblasts become surrounded by bone they are called

osteocytes, and connect to one another by long, thin processes

through the bony matrix

The epiphyses (ends) of most long bones remain cartilaginous

until the first few years after birth The secondary centres of

ossi-fication appear within the epiphyses when the chondrocytes here

enter hypertrophy, enable calcification of the matrix and blood

vessels invade bringing progenitor cells that differentiate into oste­

oblasts (Figure 21.5) The entire epiphysis becomes ossified (other

than the articular cartilage surface), but a band of cartilage remains

between the diaphysis and the epiphysis This is the epiphyseal

growth plate (Figure 21.6).

The growth plates contain chondrocytes that continually pass

through the endochondral ossification processes described above

A proliferating group of chondrocytes enter hypertrophy in a

tightly ordered manner, calcify a layer of cartilage adjacent to the

diaphysis, apoptose, and this calcified cartilage is replaced by

bone In this way the long bone continues to lengthen

Bones grow in width as more bone is laid down under the peri­

osteum Bone of the medullary cavity is remodelled by osteoclasts

that binds calcium phosphate, and the matrix (osteoid) becomes

calcified

Spicules of bone form and extend out from their initial sites of ossification Other mesenchymal cells surround the new bone and become the periosteum

As more bone forms it becomes organised, and layers of compact bone form at the peripheral surfaces (aided by osteoblasts forming under the periosteum), whereas spongy trabeculated bone is constructed in between Osteoclasts are involved in resorbing and remodelling bone here to give the adult bone shape and structure

The mesenchymal cells within the spongy bone become bone marrow

Joint formation

Fibrous, cartilaginous and synovial joints also develop from mes­enchyme from 6 weeks onwards Mesenchyme between bones may differentiate to form a fibrous tissue, as found in the sutures between the flat bones of the skull, or the cells may differenti­ate into chondrocytes and form a hyaline cartilage, as found between the ribs and the sternum A fibrocartilage joint may also form, as seen in some midline joints, for example the pubic symphysis

The synovial joint is a more complex structure, comprising mul­tiple tissues Mesenchyme between the cartilage condensations of developing limb bones, for example, will differentiate into fibrob­lastic cells (Figure 21.7) These cells then differentiate further, forming layers of articular cartilage adjacent to the developing bones, and a central area of connective tissue between the bones

The edges of this central connective tissue mass become the vial cells lining the joint cavity (Figure 21.8) The central area

syno-degenerates leaving the space of the synovial joint cavity to be filled by synovial fluid In some joints, such as the knee, the central

connective tissue mass also forms menisci and internal joint ments such as the cruciate ligaments.

liga-Clinical relevance

Pregnant women require higher quantities of calcium and phos­

phorus in their diet than normal because of foetal bone and tooth development Maternal calcium and bone metabolism are signifi­cantly affected by the mineralising foetal skeleton, and maternal bone density can drop 3–10% during pregnancy and lactation, and

is regained after weaning

A lack of vitamin D, calcium or phosphorus will cause soft, weak bones to form as the osteoid is unable to calcify This leads

to deformities such as bowed legs and curvature of the spine Weak

bones are more vulnerable to fracture This is called rickets Other

conditions that interfere with the absorption of these vitamins and minerals, or malnutrition during childhood will also lead to rickets Vitamin D is required for calcium absorption across the gut

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 22.1

The sphenoid, ethmoid, occipital bones, and the

petrous parts of the temporal bones develop from

the cartilaginous part of the neurocranium

Figure 22.3

The sutures and fontanelles of the foetal skull

Figure 22.2The parietal and frontal bones form from the membranous part of the neurocranium

Figure 22.4The membranous viscerocranium forms the maxilla,mandible and zygomatic bones, and the squamousparts of the temporal bones

TemporalMandible

ParietalFrontal

Lambdoid suturePosterior fontanelleSagittal sutureAnterior fontanelleCoronal sutureMetopic suture

Growth plates have now ossified

Child

Epiphyses have now ossifiedbut growth plates remainbetween the diaphysis andthe epiphyses

Figure 22.5

Developing vertebrae form from the fusion of the caudal half of one sclerotome

and the cranial half of the next Residual parts of the notochord are left to

become the intervertebral discs

NotochordSclerotome

Nerves

Artery

Developingmuscle bulk Residual notochord– future IVD

Cranial portion

Caudal portion

Caudal portionCranial portionNervesArtery

Skeletal system Systems development 53

Time period: day 27 to birth

Introduction

Cells for the developing skeleton come from a variety of sources

We have described the development of the somites, and the sub­

division of the sclerotome (see Chapter 20) Those cells are joined

by contributions from the somatic mesoderm and migrating neural

crest cells.

Development of the skeleton can be split into two parts: the

axial skeleton consisting of the cranium, vertebral column, ribs

and sternum; and the appendicular skeleton of the limbs.

Cranium

The skull can be divided into another two parts: the neurocranium

(encasing the brain) and the viscerocranium (of the face).

Neurocranium

The bones at the base of the skull begin to develop from cells

originating in the occipital somites (paraxial mesoderm) and

neural crest cells that surround the developing brain These carti­

laginous plates fuse and ossify (endochondral ossification) forming

the sphenoid, ethmoid and occipital bones and the petrous part of

the temporal bone (Figure 22.1)

A membranous part originates from the same source and forms

the frontal and parietal bones (Figure 22.2) These plates ossify

into flat bones (through intramembranous ossification) and are

connected by connective tissue sutures

Where more than two bones meet in the foetal skull a fontanelle

is present (Figure 22.3) The anterior fontanelle is the most promi­

nent, occurring where the frontal and parietal bones meet Fonta­

nelles allow considerable movement of the cranial bones, enabling

the calvaria (upper cranium) to change shape and pass through

the birth canal

Viscerocranium

Cells responsible for the formation of the facial skeleton originate

from the pharyngeal arches (see Chapters 38–41), and the viscero­

cranium also has cartilaginous and membranous parts during

development The cartilaginous viscerocranium forms the stapes,

malleus and incus bones of the middle ear, and the hyoid bone and

laryngeal cartilages The squamous part of the temporal bone

(later part of the neurocranium), the maxilla, mandible and zygo­

matic bones develop from the membranous viscerocranium (Figure

22.4)

Vertebrae

In week 4, cells of the sclerotome migrate to surround the noto­

chord Undergoing reorganisation they split into cranial and

caudal parts (Figure 22.5)

The cranial half contains loosely packed cells, whereas the

caudal cells are tightly condensed The caudal section of one scle­

rotome joins the cranial section of the next sclerotome This creates

vertebrae that are ‘out of phase’ with the segmental muscles that

reach across the intervertebral joint When these muscles contract

they induce movements of the vertebral column

Axial bones

Ribs also form from the sclerotome; specifically, the proximal ribs

from the ventromedial part and the distal ribs from the ventrola­

teral part (Figure 20.4) The sternum develops from somatic meso­

derm and starts as two separate bands of cartilage that come

together and fuse in the midline

Appendicular bones

Endochondral ossification of the long bones begins at the end of

week 7 The primary centre of ossification is the diaphysis and by

week 12 primary centres of ossification appear in all limb long bones (Figure 22.6)

The beginning of ossification of the long bones marks the end

of the embryonic period Ossification of the diaphysis of most long bones is completed by birth, and secondary centres of ossifica­

tion appear in the first few years of life within the epiphyses

(Figure 22.6)

Between the ossified epiphysis and diaphysis the cartilaginous

growth plate (or epiphyseal plate) remains as a region of continuing

endochondral ossification New bone is laid down here, extending the length of growing bones

At around 20 years after birth the growth plate also ossifies, allowing no further growth and connecting the diaphysis and epi­physis (Figure 22.6)

Clinical relevance

Cranium Craniosynostosis is the early closure of cranial sutures, causing an

abnormally shaped head This is a feature of over 100 genetic syndromes including forms of dwarfism It may also result in underdevelopment of the facial area

Neural crest cells are often associated with cardiac defects and facial deformations due to failed migration or proliferation Neural crest cells are also vulnerable to teratogens Examples

of cranial skeletal malformations include: Treacher Collins

syndrome (mandibulofacial dysotosis), which describes underde­

veloped zygomatic bones, mandible and external ears; Robin sequence of underdeveloped mandible, cleft palate and posteri­ orly placed tongue; DiGeorge syndrome (small mouth, widely

spaced down­slanting eyes, high arched or cleft palate, malar flat­ness, cupped low­set ears and absent thymus and parathyroid glands)

Vertebrae Spina bifida is the failure of the vertebral arches to fuse in the lumbosacral region There are two types Spina bifida occulta

affects only the bony vertebrae The spinal cord remains unaf­fected but is covered with skin and an isolated patch of hair This

can be treated surgically Spina bifida cystica (meningocoele and

myelomeningocoele) occurs with varying degrees of severity The neural tube fails to close leaving meninges and neural tissue exposed Surgery is possible in most cases but, because of the increased severity of cystica, continuous follow­up evaluations are necessary and paralysis may occur It is currently possible to detect spina bifida using ultrasound and foetal blood alpha­fetoprotein levels

Pregnant women and those trying to be come pregnant are advised to take 0.4 mg/day folic acid as it significantly reduces the risk of spina bifida Folates have an important role in DNA, RNA and protein synthesis

Scoliosis is a condition of a lateral curvature of the spine that

may be caused by fusion of vertebrae, or by malformed vertebrae The range of treatments for congenital scoliosis includes physio­

therapy and surgery Klippel–Feil syndrome is a disease where cer­

vical vertebrae fuse Common signs include a short neck and restricted movement of the upper spine

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 23.1

Regions of mesoderm

Figure 23.2Regions of a somite

Figure 23.3

Derivatives of a somite

Figure 23.5

Cells of the myotome have migrated and differentiated to

form the 3 layers of muscle of the body wall (intercostal

muscles in the thorax, external oblique, internal oblique and

transversus abdominus muscles in the abdomen)

Figure 23.9

Note where the splanchnic mesoderm is This will form

smooth muscle and cardiac muscle

Figure 23.4Cells of the myotome begin to migrate (transverse section of the embryo)

Figure 23.6Skeletal muscle Myoblasts congregate (a), fuse (b) and form a longmultinucleate muscle cell (c) (myocyte)

Figure 23.7Smooth muscle Splanchnic mesoderm forms myoblasts (a) that differentiateinto the adult pattern of separate, elongated smooth muscle cells (b)(a)

Early somite Mature somite

Neural tubeSomitocoel

DermatomeSyndetomeMyotome

Dorsal aortaSclerotomeSyndetome

Intrinsic back musclesDermis

Limb musclesVentrolateral wall muscles

Connective tissueVertebral arch

Vertebral bodyConnective tissue

Paraxial

Intermediate

Mesoderm

LateralEndodermEctoderm

Tendon

Tendon

Dorsal part

of myotomeNeural tube

Ventral part

of myotomeGut tube

Muscular system Systems development 55

Time period: day 22 to week 9

Introduction

Most muscle cells originate from the paraxial mesoderm (Figure

23.1), and specifically the myotome portion of the somites The

three types of muscle described here are skeletal, smooth and

cardiac muscle

Skeletal muscle

Within each somite the myotome splits into two muscle-forming

parts: a ventrolateral edge and a dorsomedial edge (Figures 23.2

and 23.3) The ventrolateral edge cells will form the hypaxial

mus-culature (i.e that of the ventral body wall and, in the limb regions,

musculature of the limbs) (Figures 23.4 and 23.5) The

dorsome-dial edge will form the epaxial musculature (the back muscles).

During formation of skeletal muscle multiple myoblasts (muscle

precursor cells) fuse to form myotubes at first, and then long

multinucleated muscle fibres (Figure 23.6) By the end of month

3, microfibrils have formed and the striations of actin and myosin

patterning associated with skeletal muscle are visible Important

genes involved in myogenesis include MyoD and Myf5, which

cause mesodermal cells to begin to differentiate into myoblasts,

and then MRF4 and Myogenin later in the process.

A fourth part of the somite, the syndetome, has been recently

shown to contain precursor cells of tendons (Figures 23.2 and

23.3) The cells of the syndetome lie at the ventral and dorsal edges

of the somites between the cells of the myotome and sclerotome;

blocks of cells whose tissues they will connect They also migrate,

but develop independently of muscles and connect later in

devel-opment However, tendon cells will also arise from lateral plate

mesoderm to populate the limbs, so the full story of tendon

devel-opment is not limited to the somite

Limbs

The upper limb bud is visible from day 26 around the levels of

cervical somite 5 to thoracic somite 3 The lower limb starts at the

level of lumbar somite 2 and finishes between lumbar 5 and sacral

2 (see Figure 24.1) The migrating muscle precursors migrate into

the limbs, coalesce and form specific muscle masses which then

split to form the definitive muscles of the limbs (see Chapter 24)

It is known that, as in skeletal development, cell death is important

in the development of these muscle masses Joints within the limbs

develop independently from the musculature (see Chapter 21) but

foetal musculature and the motions that occur are required to

retain the joint cavities

Neurons of spinal nerves that follow migrating myoblasts are

specific to their original segmental somites By roughly 9 weeks

most muscle groups have formed in their specific locations The

migration of whole myotomes and fusion between them accounts

for the grouping of muscular innervation seen in adult limb

anatomy

Movements of the limbs can be detected using ultrasound at 7

weeks and isolated limb movements from around 10–11 weeks

Head

In the head area the somitomeres undergo similar changes but

never fully develop the three compartments of the somite, and this

process remains less well understood

Myogenesis in the head differs from trunk and limb myogenesis

as these muscles have different phenotypic properties, although myoblasts still develop from the paraxial mesoderm of the somito-meres and migrate into the pharyngeal arches and their terminal locations

The surrounding connective tissues coordinate migration and differentiation of muscle as elsewhere, but the nerves to these muscles are present before their formation, as they are cranial nerves Musculature formed from pharyngeal arches and their innervation is described in Chapters 38–41

Extraocular muscles probably arise from mesenchyme near the

prechordal plate (a thickening of endoderm in the embryonic head) Muscles of the iris are derived from neuroectoderm, whereas ciliary muscle is formed by lateral plate mesoderm Muscles of the

tongue form from occipital somites, as does the musculature of the

pharynx Movement of the mouth and tongue and the ability to swallow amniotic fluid begins around week 12

Smooth muscle

Most smooth muscle of the viscera and gastrointestinal tract

(Figure 23.7) is derived from splanchnic mesoderm that is located

where the organs are developing (Figure 23.8) Developing blood vessels surround local mesenchyme that forms smooth muscle Larger blood vessels (aorta and pulmonary vessels) receive contri-

butions from neural crest cells.

Exceptions to the splanchnic mesoderm rule include muscles of the pupil, erector pili muscles of hair, salivary glands, lacrimal glands, sweat glands and mammary gland smooth muscle, all of

which are derived from ectoderm.

At approximately 22 days a cardiac tube has formed that can contract (see Chapter 25)

Clinical relevance

Muscular dystrophy is a group of over 20 muscular diseases that

have genetic causes and all produce progressive weakness and wasting of muscular tissue

Duchenne muscular dystrophy affects boys (in extremely rare

cases symptoms show in female carriers) and affects the gene coding for the protein dystrophin Patients develop problems with walking between 1 and 3 years of age, wheelchairs are necessary between 8 and 10 years, and life expectancy is limited to late teens

to early adulthood as cardiac muscle is affected in the later stages

of the disease There is no cure but research into using stem cells

in forms treatment is ongoing

An absence or partial absence of a skeletal muscle can occur

(e.g Poland anomaly which exhibits a unilateral lack of pectoralis

major) Other commonly affected muscles include quadriceps femoris, serratus anterior, latissimus dorsi and palmaris longus, and are relatively common

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 24.1

The limb buds appear at the end of the 4th week,

grow and are clearly recognisable by the middle

of the 5th week

Figure 24.4

Condensations of mesenchyme form

digital rays, and the cells in between

die by apoptosis

Figure 24.7Dermatomes of the upperlimb bud

Figure 24.8The limbs bend and rotate

Figure 24.5Digits form as the shape of the handemerges

Formation of the digits

Figure 24.3The zone of polarising activity organises cells of the limbbud in a cranial–caudal manner, which will arrange thedevelopment of structures that form the different digits,for example

Figure 24.6

Cells from a somite’s myotome

migrate into the limb bud

Axons of motor and sensory

neurones follow

Figure 24.9The migrating myotomes and neurones maintaintheir segmented pattern in the early limb bud,but this is altered with growth and rotation

of the limb

Figure 24.2The cells of the apical ectodermalridge induce proliferation of themesenchymal cells of the progresszone, causing the limb bud to growdistally

Patterning of the limb bud

Zone of polarisingactivity

Cranial Cranial – caudal

organisation

Caudal

C3 C2C4 T2 T3 T4 T5 T7 T8 T9 T10 T11 T12 L1

L2

C5

C6 C7 T1

C8

T6

Neural tubeSomiteDermatomeMyotome

C5

C6 C7 C8 T1

Lower limb budSomites

Webbingbetweendigits

Upper limb bud

ApoptoticcellsDigitalrays

Apicalectodermalridge

Progresszone

Time period: week 4 to adult

Introduction

Limb development has been studied in great detail, although it is

not entirely clear how it is initiated The mechanisms by which the

cells of the early limb are organised, and the fates of those cells,

have been explored for decades, as aberrations of these processes cause gross limb abnormalities

Limb buds

Cells in the lateral mesoderm at the level of C5–T1 begin to form the upper limb buds at the end of the fourth week and they are

Musculoskeletal system: limbs Systems development 57

visible from around day 25 The lower limb buds appear a couple

of days of later at the level of L1–L5 (Figure 24.1)

Each limb bud has an ectodermal outer covering of epithelium

and an inner mesodermal mass of mesenchymal cells

Distal growth

A series of reciprocal interactions between the underlying

meso-derm and overlying ectomeso-derm result in the formation of a

thick-ened ridge of ectoderm called the apical ectodermal ridge (AER;

Figure 24.2) This ridge forms along the boundary between the

dorsal and ventral aspects of the limb bud

The AER forms on the distal border of the limb and induces

proliferation of the underlying cells via fibroblast growth factors

(FGF), inducing distal outgrowth of the limb bud This area of

rapidly dividing cells is called the proliferating zone (PZ; Figure

24.2) As cells leave the PZ and become further from the AER they

begin differentiation and condense into the cartilage precursors of

the bones of the limb Endochondral ossification of these bones is

described in Chapter 21

Organisation

Patterning within the early limb bud controls the proliferation

and differentiation of mesenchymal cells, forming the structures

of the limb The AER controls the proximal–distal axis, for

example

A group of cells in the caudal mesenchyme of the limb bud act

as a zone of polarising activity (ZPA; Figure 24.3), secreting a

morphogen that diffuses cranially and themselves contributing to

development of the digits The ZPA has a role in a cranial–caudal

axis (i.e specifying where the thumb and little finger form; Figure

24.3)

The dorsal–ventral axis is controlled by signals from the dorsal

and ventral ectoderm These signals specify which side of the hand

the nails should form on and which side the fingertips, for example

Disruption of these patterning signals (and others) causes limb

malformations

Digits

During weeks 6 and 7 (development of the lower limbs lags behind

that of the upper limbs) the distal edges of the limb buds flatten

to form hand and foot plates Digits begin to develop as

condensa-tions of mesenchymal cells clump together to construct long

thick-enings (Figure 24.4) Localised programmed cell death between

these digit primordia splits the plate into five digital rays, and the

mesenchymal condensations develop to become the bones and

joints of the phalanges (Figures 24.4 and 24.5)

Dermatomes and myotomes

Cells from the dermamyotomes of somites (see Chapter 20) at the

levels of the limb buds migrate into the limbs, and differentiate

into myoblasts They group to form dorsal and ventral masses,

which will approximate to the muscles of the flexor and extensor

compartments of the adult

Motor neurons from the ventral rami of the spinal cord at the

levels of the limb buds (C5–T1 for the upper limbs, L4–S3 for the

lower limbs) extend axons into the limbs, following the myoblasts (Figure 24.6) Control of this axon growth also occurs independent

of muscle development, however Dorsal branches from each ventral ramus pass to muscles of the dorsal mass (extensors), and ventral branches from each ventral ramus pass to the ventral mass (flexors) Also, more cranial neurons (C5–C7 in the upper limb, for example) pass to craniodorsal parts of the limb bud, and more caudal neurons (C8–T2) pass to ventrocaudal parts

As axons enter the limb bud they mix to create the brachial and lumbosacral plexuses during this development stage, before the axons continue onwards to their target muscles Branches combine

to form larger dorsal and ventral nerves, eventually the radial, musculocutaneous, ulnar and median nerves in the upper limb, for example The radial nerve forms from dorsal branches, as it is a nerve that innervates the extensor muscles of the upper arm and forearm

The muscle groups, initially neatly organised, fuse and adult muscles may be derived from myoblasts from multiple somites Likewise, axons of the dorsal root ganglia initially carry sensory innervation from the skin of the limb in an organised pattern of dermatomes

The upper limb begins to become flexed at the elbow, and the lower limb develops a bend at the knee in week 7 The limbs also rotate, transforming from a simple, outwardly extending limb bud

to a more recognisable limb shape The upper limb rotates laterally

by 90° and the lower limb rotates medially by 90° (Figure 24.7)

By the end of week 8 the upper and lower limbs are well defined, with pads on the fingers and toes The hands meet in the midline, and the feet have become close together

With the rotation and bending of the limbs, and the fusing

of early muscles, the patterns of muscle innervation and matomes are disrupted and produce the adult patterns (Figures 24.7–24.9)

der-Clinical relevance

The period of early limb development of weeks 4 and 5 is tible to interruption by teratogens, as seen in the thalidomide epidemic of congenital limb abnormalities of the 1950s and 1960s The earlier the teratogen is applied to the foetus, the more severe the developmental defects

suscep-Achondroplastic dwarfism is caused by a mutation in the

fibrob-last growth factor receptor 3 gene (FGFR3) FGF signalling via

this receptor is involved in growth plate function, and disruption

of this causes limited long bone growth and disproportionate short stature

Meromelia describes the partial absence of a limb, and amelia the complete absence of a limb Phocomelia refers to a limb in

which the proximal part is shortened, and the hand or foot is attached to the torso by a shortened limb

In polydactyly an extra digit, often incomplete, forms on the hand or foot Ectrodactyly describes missing digits, and often

lateral digits forming a claw-shaped hand or foot A hand or foot

with brachydactyly has shortened digits A person with syndactyly

has webbed digits as the interdigital cells failed to apoptose normally

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Vasculogenesisforming bloodislands in themesoderm

Figure 25.1

Blood islands appear in the lateral plate mesoderm from

angioblasts that join together as a syncytium (week 3)

Figure 25.2

Location of the endocardial tube and myocardial cells in the

embryo before the embryo begins folding Transverse section

Figure 25.3Anterior position of the endocardial tube surrounded by the pericardialcavity relative to the gut, in cross section at 22 days

Insert: Region of cross section

Figure 25.4

The early heart tube (22 days) Figure 25.5The folded heart tube (29 days)

Neural plate

EctodermMesodermNotochord

Dorsalaorta EndodermMyocardial cells

Endocardial tube

Embryonic

folding

Dorsal aortaNotochord

GutPericardial cavityEndocardial tube

Pericardialcavity

Endocardialtube

Bulbus cordisVentricleAtriumSinus venosus

Truncus arteriosus

Bulbus cordisVentricle

Left atriumTruncus arteriosus

Circulatory system: heart tube Systems development 59

Time period: days 16–28

Formation of the heart tube

During the third week of development blood islands appear in the

lateral plate mesoderm (Figure 25.1) from angioblasts that

accu-mulate as a syncytium (rather like the formation of the

syncytio-trophoblast that we saw form during the development of the

placenta in Chapter 12) From these cells new blood cells and

blood vessels form through vasculogenesis Blood islands at the

cranial end of the embryo merge and assemble a horseshoe-shaped

tube lined with endothelial cells which curves around the embryo

in the plane of the mesoderm

Progenitor cells that migrated from the epiblast differentiate in

response to signals from the nearby endoderm to become

myob-lasts and surround the horseshoe-shaped tube (Figure 25.2) This

developing cardiovascular tissue is called the cardiogenic field.

The early heart tube expands into the newly forming pericardial

cavity (Figure 25.3) as it begins to link with the paired dorsal

aortae cranially and veins caudally The developing central nervous

system and folding of the embryo (see Chapter 18) pushes it into

the thorax and brings the developing parts of the cardiovascular

system towards one another (Figures 25.1–25.3)

Looping and folding of the heart tube

The early, simple heart tube (Figure 25.4) undergoes a series of

foldings to bring it from a straight tube to a folded shape ready to

become four chambers The heart tube begins to bend at 23 days

(stops at 28 days) and develops two bulges The cranial bulge is

called the bulbus cordis and the caudal one is the primitive ventricle

(Figure 25.5) These continue to bend and create the cardiac (or

bulboventricular) loop during the fourth week of development.

When the heart tube loops, the top bends towards the right so

that the bulboventricular part of the heart becomes U-shaped

This looping changes the anterior–posterior polarity of the heart

into the left–right that we see in the adult The bulbus cordis forms

the right part of the ‘U’ and the primitive ventricle the left part

You can see the junction between the bulbus cordis and ventricle

by the presence of the bulboventricular sulcus The looping causes

the atrium and sinus venosus to move dorsal to the heart loop.The atrium is now dorsal to the other parts of the heart and the common atrium is connected to the primitive ventricle by the

atrioventricular canal The primitive ventricle will develop into

most of the left ventricle and the proximal section of the bulbus

cordis will form much of the right ventricle The conus cordis will

form parts of the ventricles and their outflow tracts, and the

truncus arteriosus will form the roots of both great vessels.

Sinus venosus (right atrium)

The sinus venosus comprises the inflow to the primitive heart tube

and is formed by the major embryonic veins (common cardinal, umbilical and vitelline) as they converge at the right and left sinus horns (see Chapter 28) The sinus venosus passes blood from the veins to the primitive atrium

With time, venous drainage becomes prioritised to the right side

of the embryo and the left sinus horn becomes smaller and less significant, eventually forming the coronary sinus and draining the coronary veins into the right atrium The right sinus horn persists,

enlarges and becomes part of the inferior vena cava entering the

heart and incorporated into the right atrium, forming much of its wall

Similarly, a single pulmonary vein is initially connected to the left side of the primitive atrium and divides twice during the fourth week to form four pulmonary veins These become incorporated into the wall of the future left atrium and extend towards the developing lungs

Clinical relevance

Many congenital heart defects occur later in development during the division of the heart into its four chambers

Dextrocardia is a condition in which the heart lies on the right,

with the apex of the left ventricle pointing to the right, instead of

the left This is often associated with situs inversus, a condition in

which all organs are asymmetrical Other congenital heart defects can occur with dextrocardia but it is often asymptomatic

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

LVLV

Figure 26.1

The endocardial cushions split the single atrioventricular canal

into 2 canals linking the atrium and ventricle (weeks 5 and 6)

Figure 26.3

The formation of the interventricular septum (weeks 5 to 7)

Figure 26.2The formation of the atrial septa (weeks 5 and 6)

Figure 26.4The single outflow tract of the conus arteriosus and truncusarteriosus is split into 2 by the conotruncal septum

Figure 26.5The adult pulmonary trunk and aorta twist around each other as they rise superiorly from the ventricles

PulmonarytrunkAorta

Outflow Outflow

Common atrioventricularcanal

Endocardialcushions

Septum primumSeptum secundum

Septum secundumOstium secundum

Foramen ovaleLA

Endocardial cushion

SuperiorInferior

Left and rightatrioventricular canals

EndocardialcushionsSuperior

Inferior

Septum primum

InterventricularforamenInterventricularseptum

Membranous partMuscular part

Circulatory system: heart chambers Systems development 61

Time period: day 22

Dividing the heart into chambers

Heart septa appear during week 5 and divide the heart tube into

four chambers between days 27 and 37 The septa form as inward

growths of endocardium separating the atrial and ventricular

chambers, splitting the atrium into left and right, and splitting the

ventricle and bulbus cordis into left and right ventricles,

respec-tively (Figure 26.1)

The atrioventricular canal connects the primitive atrium and

ventricle At the end of week 4 the endocardium of the anterior

and posterior walls of the atrioventricular canal thicken and bulge

outwards into the canal’s lumen These are the endocardial

cush-ions and by the end of week 6 they meet in the middle, splitting

the atrioventricular canal into two canals (Figure 26.1)

Atria

At the same time, new tissue forms in the roof of the primitive

atrium This thin, curved septum is the septum primum and extends

down from the roof, growing towards the endocardial cushions

The primitive atrium begins to split into left and right atria The

gap remaining inferior to the septum primum is the ostium primum

(Figure 26.2) Growth of the endocardial cushions and the septum

primum cause them to meet

A second ridge of tissue grows from the roof of the atrium, on

the right side of the septum primum This is called the septum

secundum (Figure 26.2) and grows towards the endocardial

cush-ions, but stops short The gap remaining is the ostium secundum,

and the two holes and flap of the septum primum against septum

secundum form a one-way valve allowing blood to shunt from the

right atrium to the left but not in reverse This is the foramen ovale

(Figure 26.2) and is one of the routes that exist before birth

allow-ing blood circulation to circumvent the developallow-ing lungs A change

in pressure between atria at birth holds the septum primum closed

against the septum secundum, and the foramen becomes

perma-nently sealed

Ventricles

From the end of the fourth week a muscular interventricular septum

arises from the floor of the ventricular chamber as the two

primi-tive ventricles begin to expand (Figure 26.3) The septum rises

towards the endocardial cushions, leaving an interventricular

foramen As the atrioventricular septum is completed late in the

seventh week the endocardial cushion extends inferiorly (as the

membranous interventricular septum) to complete the

interventricu-lar septum and close the interventricuinterventricu-lar foramen (Figure 26.3).

Now the heart is four connected chambers with two input tubes

The single outflow tract of the primitive heart must also split into

two to pass blood from the ventricles to the pulmonary and

sys-temic circulatory systems (Figure 26.4) The conotruncal outflow

tract, comprising the conus arteriosus and truncus arteriosus,

devel-ops a pair of longitudinal ridges on its internal surface These grow

towards one another and fuse to form the conotruncal septum,

which meets with the muscular interventricular septum to link each ventricle with its outflow artery The conotruncal septum spirals within the conus arteriosus and truncus arteriosus, giving the inter-twining nature of the adult pulmonary trunk and aorta (Figure 26.5)

Valves

After the fusion of the endocardial cushions to form two entricular canals, mesenchymal cells proliferate in the walls of the canals The ventricular walls inferior to this erode, leaving leaflets

atriov-of primitive valves and thin connections to the walls atriov-of the

ventri-cles These connections develop into the fibrous chordae tendinae with papillary muscles at their ventricular ends The left atrioven- tricular valve develops two leaflets (the bicuspid valve) and the right atrioventricular valve usually develops three (the tricuspid

valve)

The semilunar valves of the aorta and pulmonary trunk develop

in a similar manner during the formation of the conotruncal septum.

Neural crest cells

Neural crest cells, appearing during neurulation, migrate from the developing neural tube to take part in the development of an astounding range of different structures, including the heart In the heart they contribute to the conotruncal septum

Clinical relevance

Heart defects are the most common congenital defects, generally occurring because of problems with structural development proc-esses Six in 1000 children are born with a heart defect

A ventricular septal defect is the most common heart defect, and

failure of the membranous interventricular septum to close pletely allows blood to pass from the left to right ventricles Most will close on their own but surgery may be required This can be

com-linked to other conotruncal defects Atrial septal defects occur

when the foramen ovale fails to close (patent foramen ovale), allowing blood to pass between atria after birth Treatment is surgical

Abnormal narrowing of the pulmonary or aortic valves can give

pulmonary or aortic stenosis, forcing the heart to work harder

Stenosis of the aorta will limit the systemic circulation, with clear consequences These arteries can be transposed if the conotruncal septum fails to form its spiral course, and the aorta will arise from the right ventricle and the pulmonary trunk from the left ventricle (transposition of the great vessels) Low oxygen blood is passed into the systemic circulation

Tetralogy of Fallot describes four congenital defects resulting

from abnormal development of the conotruncal septum: nary stenosis, an overriding aorta connected to both ventricles, a ventricular septal defect and hypertrophy of the wall of the right ventricle Poorly oxygenated blood is pumped in the systemic cir-culation with symptoms of cyanosis and breathlessness Surgical intervention is required

pulmo-Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 27.1

The primitive blood vessels of the embryo at around 28 days

Figure 27.3

The adult anatomy of the major arteries of the

upper thorax and neck

Figure 27.2The aortic arch arteries (found in the pharyngeal arches)form important arteries in the head, neck and thoraxHeart

Aorta

Pulmonary artery

Common carotid artery

Primitive heart tube

Dorsal aortaVitelline veins

Heart

Heart

Aortic arches

III IV VI

Internal carotid arteryExternal carotid artery

Circulatory system: blood vessels Systems development 63

Time period: day 18 to birth

Vasculogenesis

Vasculogenesis is the formation of new blood vessels from cells

that were not blood vessels before As if by magic, blood cells and

vessels appear in the early embryo In fact, mesodermal cells are

induced to differentiate into haemangioblasts, which further

dif-ferentiate into both haematopoietic stem cells and angioblasts

Haematopoietic stem cells will form all the blood cell types, and

angioblasts will build the blood vessels Separate sites of

vasculo-genesis may merge to form a network of blood vessels, or new

vessels may grow from existing vessels by angiogenesis When the

liver forms it will be the primary source of new haematopoietic

stem cells during development

Angiogenesis

Angiogenesis is the development of new blood vessels from

exist-ing vessels Endothelial cells detach and proliferate to form new

capillaries This process is under the influence of various chemical

and mechanical factors Although important in growth this also

occurs in wound healing and tumour growth, and as such

angio-genesis has become a target for anti-cancer drugs

Primitive circulation

Near the end of the third week blood islands form through

vascu-logenesis on either side of the cardiogenic field and the notochord

(see Chapter 25) They merge, creating two lateral vessels called

the dorsal aortae (Figure 27.1) These blood vessels receive blood

from three pairs of veins, including the vitelline veins of the yolk

sac (a site of blood vessel formation external to the embryo), the

cardinal veins and the umbilical veins (Figure 27.1).

Blood flows from the dorsal aortae into the umbilical arteries

and the vitelline arteries Branches of the dorsal aortae later fuse

to become the single descending aorta in adult life

The heart tube will form where veins drain to the dorsal aortae

The aortic arches within the pharyngeal arches form here, linking

the outflow of the primitive heart to the dorsal aortae Blood flow

begins during the fourth week

Aortic arches

Five pairs of aortic arches form between the most distal part of

the truncus arteriosus and the dorsal aortae They develop within

the pharyngeal arches during weeks 4 and 5 of development and

are associated with other structures derived from the pharyngeal

arches in the head and neck

The aortic arches grow in sequence and therefore are not all

present at the same time One little mystery in embryology is that

the fifth aortic arch (and pharyngeal arch) either does not form or

it grows and then regresses For that reason the five aortic arch

arteries that do develop are named I, II, III, IV and VI (Figure

27.2)

The truncus arteriosus also divides and develops into the ventral

part of the aorta and pulmonary trunk Its most distal part forms

left and right horns that also contribute to the brachiocephalic

artery

The five aortic arches and paired dorsal aortae combine and develop into a number of vessels of the head and neck (Figure 27.3):

Aortic arch I Maxillary arteryAortic arch II Stapedial artery (rare)Aortic arch III Common carotid artery and internal carotid

artery (external carotid artery is an angiogenic branch of aortic arch III)

Aortic arch IV Right side, right subclavian artery (proximal

portion)Left side, aortic arch (portion between the left common carotid and subclavian arteries)Aortic arch VI Right side, right pulmonary artery

Left side, left pulmonary artery and ductus arteriosus

Ductus arteriosus

Aortic arch VI forms as a link between the truncus arteriosus and the left dorsal aorta (Figure 27.2); this link persists until birth as the ductus arteriosus This vessel allows blood flow to bypass the lungs as it connects the pulmonary trunk with the aorta Foetal pulmonary vascular resistance is high and most blood from the right ventricle (85–90%) passes through the ductus arteriosus to the aorta Blood flow to the lungs is minimal during gestation and they are protected from circulatory pressures during development This shunt also allows the wall of the left ventricle

to thicken

Coronary arteries

The blood supply to the tissue of the heart has been considered to form by angiogenesis from the walls of the right and left aortic sinuses (bulges in the aorta that occur just superior to the aortic valve) This may be influenced by specific tension in the walls of the heart Vessels form that link with a plexus of epicardial vessels

on the surface of the heart The reverse may be true, however, and these arteries may grow from the epicardial plexus into the aorta and right atrium to initiate their function Recently, cells from the sinus venosus have been tracked as angiogenic sprouts that migrate over the myocardium and form both coronary arteries and veins and these cells may, in fact, be the source of all the coronary blood vessels

Clinical relevance

Coarctation of the aorta is a narrowing of the aorta sometimes

found distal to the point from which the left subclavian artery arises It may be described as preductal or postductal depending upon its location relative to the ductus arteriosus With postductal coarctation, a collateral circulation develops linking the aorta proximal to the ductus arteriosus with inferior arteries With a preductal coarctation the route of blood flow through the ductus arteriosus to inferior parts of the body is lost with birth causing hypoperfusion of the lower body

Aberrations in aortic arch development may give anomalous arteries, such as a right arch of the aorta or a vascular ring around the trachea and oesophagus

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

CommoncardinalveinAnterior cardinal vein

Posterior cardinal vein

Internal jugular vein(anterior cardinal vein)Superior vena cava

(anterior cardinal vein)

Subclavian vein Azygos and hemiazygos veins

(supracardinal veins)Inferior vena cava

(vitelline vein, subcardinalvein, supracardinal vein)

Left brachiocephalic vein(anterior cardinal veins)

Renal vein(subcardinal vein)

Common iliac veinFigure 28.4

Supracardinalvein

Figure 28.2Veins at 28 days

Anterior cardinal vein

Heart(Head)

Sinus venosusVitelline veinUmbilical vein

Posterior cardinal vein

Circulatory system: embryonic veins Systems development 65

Time period: day 18 to birth

Vitelline vessels

The vitelline circulation is the flow of blood between the embryo

and the yolk sac through a collection of vitelline arteries and veins

that pass within the yolk stalk (Figure 28.1)

The vitelline arteries are branches of the dorsal aortae, and most

of them degenerate in time Those that remain fuse and form the

3 unpaired ventral arterial branches of the aorta that supply the

gut: the celiac trunk, superior mesenteric artery and inferior

mesenteric artery

The vitelline veins will give rise to the hepatic portal vein and

the hepatic veins of the liver

Umbilical vessels

The umbilical circulation is the flow of blood between the chorion

of the placenta and the embryo The umbilical arteries carry poorly

oxygenated blood to the placenta and the veins carry highly

oxy-genated blood initially to the heart of the embryo (Figure 28.1),

and later into the liver when it forms (see Figure 29.1) The right

umbilical vein is lost around week 7, leaving only the left to carry

blood from the placenta

The formation of the ductus venosus during the foetal period

causes about half of the blood from the umbilical vein to flow

directly into the inferior vena cava, bypassing the liver (Figure

29.1) This, with other mechanisms, preferentially shunts highly

oxygenated blood to the foetal brain

Of the umbilical arteries only the proximal portions persist as

parts of the internal iliac arteries and superior vesical arteries in

the adult The distal portions do not remain as arteries but become

the medial umbilical ligaments The umbilical vein becomes the

ligamentum teres, passing from the umbilicus to the porta hepatis

in the adult (see Chapter 29)

Cardinal veins

The common cardinal veins initially form an H-shaped structure,

with the horizontal bar being the sinus venosus that links the major

veins and the atrium of the early heart tube (Figure 28.2) The left

and right anterior (or superior) branches drain blood from the

head and shoulder regions and the posterior (or inferior) branches

drain from the abdomen, pelvis and lower limbs

At 6 weeks a subcardinal vein arises on either side of the embryo

caudal to the heart and anastomoses with the posterior cardinal veins (Figure 28.3) The subcardinal veins also form an anastomo-sis with each other anterior to the dorsal aortae, and tributaries are sent into the developing limbs The right subcardinal vein joins

vessels of the liver Similarly, at 7 weeks supracardinal veins form

and link to the posterior cardinal veins (Figure 28.3)

The posterior cardinal veins degenerate, although the most caudal parts continue as a sacral venous plexus and later as the common iliac veins

An important junction between the right supracardinal and right subcardinal vein forms and both will become sections of the inferior vena cava (IVC) Parts of the right posterior cardinal veins, common, subcardinal and supracardinal veins also contrib-ute A shift towards the right side occurs, with degeneration of venous structures on the left side and the formation and enlarge-ment of the inferior vena cava on the right (Figure 28.4)

Similarly, the degeneration of much of the left anterior cardinal vein gives a shift to the right side as the right anterior cardinal vein forms part of the superior vena cava (SVC) and the right brachio-cephalic vein (Figure 28.4) An anastomosis between the 2 anterior cardinal veins persists as the left brachiocephalic vein

The right supracardinal vein becomes much of the azygos vein, and the left supracardinal vein forms part of the hemiazygos vein

and the accessory hemiazygos veins (Figure 28.4) Branches from the subcardinal vein network form renal, suprarenal and the gonadal veins

Clinical relevance

The formation of the venous system is somewhat variable and complicated, and can give rise to variations in adult SVC and IVC anatomy The hepatic section of the IVC may fail to form, for example, and blood instead flows back to the heart through the azygos and hemiazygos veins from the inferior parts of the body

(azygos continuation) Persistence of supracardinal veins can leave double inferior vena cavae, and persistence of the left anterior car- dinal vein can give double SVC In this case the right anterior vena cava may even degenerate, leaving only a left SVC These varia-

tions are not common

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 29.1

The foetal circulatory system Half of the blood from the umbilical vein bypasses the

liver via the ductus venosus Oxygen saturation of the blood leaving the heart is

reduced by blood entering from the superior vena cava and the coronary sinus

Pulmonary trunk

Pulmonaryvessels

Superiorvena cava

Inferiorvena cava

Figure 29.2The foetal circulation, a closer view of the heart

Right atrium

Rightventricle

Common carotid artery

Internal jugular vein Subclavian artery

Superior vena cava

Inferior vena cavaCommon iliac vessels

Well oxygenated blood flow Fairly well oxygenated blood flow Less well oxygenated blood flow Poorly oxygenated blood flow

Ductus venosus

Pulmonary trunkDuctus arteriosus

Ductus arteriosus(closed)

Figure 29.4Neonatal circulation, a closer view of the heart

Fossa ovale(closed)

Figure 29.5

Neonatal circulation At birth the lungs begin to function, the ductus

arteriosus and ductus venosus close, and the umbilical vessels close

Ductus arteriosus(closed)

Ductus venosus

(closed)

Umbilical arteries(closed)

Circulation system: changes at birth Systems development 67

Time period: birth (38 weeks)

Foetal blood circulation

Dramatic and clinically significant changes occur to the circulatory

and respiratory systems at birth Here, we look at changes

prima-rily of the circulatory system and how these changes prepare the

baby for life outside the uterus

If we were to follow the flow of oxygenated blood in the foetus

from the placenta (Figure 29.1), we would start in the umbilical

vein and track the blood moving towards the liver Here, half the

blood enters the liver itself and half is redirected by the ductus

venosus directly into the inferior vena cava, bypassing the liver

The blood remains well oxygenated and continues to the right

atrium, from which it may pass into the right ventricle in the

expected manner or directly into the left atrium via the foramen

ovale (Figure 29.2) Blood within the left atrium passes to the left

ventricle and then into the aorta

Blood entering the right atrium from the superior vena cava and

the coronary sinus is relatively poorly oxygenated The small

amount of blood that returns from the lungs to the left atrium is

also poorly oxygenated Mixing of this blood with the

well-oxy-genated blood from the ductus venosus reduces the oxygen

satura-tion somewhat

Blood within the right ventricle will leave the heart within the

pulmonary artery, but most of that blood will pass through the

ductus arteriosus and into the descending aorta Almost all of

the well-oxygenated blood that entered the right side of the heart

has avoided entering the pulmonary circulation of the lungs, and

has instead passed to the developing brain and other parts of the

body (Figure 29.3)

Ductus venosus

The umbilical arteries constrict after birth, preventing blood loss

from the neonate The umbilical cord is not cut and clipped

imme-diately after birth, however, allowing blood to pass from the

pla-centa back to the neonatal circulation through the umbilical vein

The ductus venosus shunted blood from the umbilical vein to

the inferior vena cava during foetal life, bypassing the liver After

birth a sphincter at the umbilical vein end of the ductus venosus

closes (Figure 29.4) The ductus venosus will slowly degenerate

and become the ligamentum venosus.

Once the umbilical circulation is terminated the umbilical vein

will also degenerate and become the round ligament (or

ligamen-tum teres hepatis) of the liver This may be continuous with the

ligamentum venosus The umbilical arteries will persist in part as

the superior vesical arteries, supplying the bladder, and the

remain-der will degenerate and become the median umbilical ligaments.

Ductus arteriosus

The shunt formed by the ductus arteriosus between the pulmonary

trunk and the aorta in foetal life causes blood rich in oxygen to

bypass the lungs, which have a very high vascular resistance during

development With birth, the first breath of air and early use of

the lungs the pulmonary vascular resistance drops and blood flow

to the lungs increases An increase in oxygen saturation of the blood, bradykinin produced by the lungs, and a reduction in cir-culating prostaglandins cause the smooth muscle of the wall of the ductus arteriosus to contract, restricting blood flow here and increasing blood flow through the pulmonary arteries (Figure 29.4) Physiological closure is normally achieved within 15 hours

of birth

During the first few months of life, the ductus arteriosus closes

anatomically, leaving the ligamentum arteriosum as a remnant As

this is a remnant of the sixth aortic arch the left recurrent laryngeal nerve can be found here (see Chapter 41)

Foramen ovale

The direction in which blood flows into the right atrium from the inferior vena cava and the crista dividens (the lower edge of the septum secundum, forming the superior edge of the foramen ovale) preferentially direct the flow of blood through the foramen ovale into the left atrium, reducing mixing with poorly oxygenated blood entering the right atrium from the superior vena cava (Figures 29.2 and 29.3)

As the child takes his or her first breath the reduction in nary vascular resistance and subsequent flow of blood through the pulmonary circulation increases the pressure in the left atrium As the pressure in the left atrium is now higher than in the right atrium the septum primum is pushed up again the septum secundum, thus functionally closing the foramen ovale (Figure 26.3) Anatomical closure is usually completed within the next 6 months In the adult

pulmo-heart a depression called the fossa ovalis remains upon the interior

of the right atrium

Clinical relevance

Patent foramen ovale (PFO) is an atrial septal defect The foramen

ovale fails to close anatomically although it is held closed by the difference in interatrial pressure A ‘backflow’ of blood can occur from left to right under certain circumstances which increases pressure in the thorax These circumstances include sneezing or coughing, and even straining during a bowel movement Autopsy studies have shown a PFO incidence of 27% in the US population but those with this defect generally do not have symptoms Treat-ment varies depending upon age and associated problems, but often no treatment is necessary

If the ductus arteriosus fails to close at birth it is termed a patent ductus arteriosus (PDA) Well-oxygenated blood from the aorta

mixes with poorly oxygenated blood from the pulmonary arteries, causing tachypnoea, tachycardia, cyanosis, a widened pulse pres-sure and other symptoms Longer term symptoms seen during the first year of life include poor weight gain and continued laboured breathing Premature infants are more likely to develop a PDA Treatment can be surgical or pharmacological

A portosystemic shunt is less common and occurs when the

ductus venosus fails to close at birth, allowing blood to continue

to bypass the liver A build-up of uric acid and ammonia in the blood can lead to a failure to gain weight, vomiting and impaired brain function

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 30.1

Early lung bud formation Week 4

Figure 30.2

Respiratory tree development Figure 30.3Two of the main differences between the alveoli before

and after birth are the volume of each alveolus and the thickness of the blood–air boundary

Bronchial

branching

3–16 weeks

Primitive alveolibegin to develop

Alveoli becomemature

Terminalbronchiole

FoetalThick walled sacssmaller lumen

Adultthin walled sacslarge lumen

Alveolarsac

Tracheoesophageal

Bronchialbuds

Right Left

Time period: day 28 to childhood

Introduction

The development of the respiratory system is continuous from the

fourth week, when the respiratory diverticulum appears, to term

The 24-week potential viability of a foetus (approximately 50%

chance of survival) is partly because at this stage the lungs have

developed enough to oxygenate the blood Limiters to

oxygena-tion include the surface area available to gaseous exchange, the

vascularisation of those tissues of gaseous exchange and the action

of surfactant in reducing the surface tension of fluids within the

lungs

Development of the respiratory system includes not only the

lungs, but also the conducting pathways, including the trachea,

bronchi and bronchioles Lung development can be described in

five stages: embryonic, pseudoglandular, canalicular, saccular and alveolar.

Although not in use as gas exchange organs in utero, the lungs

have a role in the production of some amniotic fluid

Lung bud

The development of the respiratory system begins with the growth

of an endodermal bud from the ventral wall of the developing gut tube in the fourth week (Figure 30.1)

To separate the lung bud from the gut tube two longitudinal folds form in the early tube of the foregut, meet and fuse, creating

the tracheoesophageal septum This division splits the dorsal

foregut (oesophagus) from the ventral lung bud (larynx, trachea and lung) These structures remain in communication superiorly through the laryngeal orifice

Respiratory system Systems development 69

Being derived from the gut the epithelial lining is endodermal in

origin, but as the bud grows into the surrounding mesoderm

recip-rocal interactions between the germ layers occur The mesoderm

develops into the cartilage and smooth muscle of the respiratory

conduction pathways

Respiratory tree

In the fifth week the tracheal bud splits and forms two lateral

outgrowths: the bronchial buds It is at this early stage we see the

asymmetry of the lungs appear; the right bud forms three bronchi

and the left two The bronchial buds branch and extend, forming

the respiratory tree of the three right lobes and two left lobes of

the lungs (Figure 30.1)

Up to week 5 the first period of lung development is known as

the embryonic stage.

From 6 weeks their development enters the pseudoglandular

stage The respiratory tree continues to lengthen and divide

with 16–20 generations of divisions by the end of this stage

(Figure 30.2) Histologically, the lungs resemble a gland at this

stage

Epithelial cells of the bronchial tree become ciliated and the

beginnings of respiratory elements appear Cartilage and smooth

muscle cells appear in the walls of the bronchi Lung-specific type

II alveolar cells (pneumocytes) begin to appear These are the cells

that will produce surfactant

The pseudoglandular stage ends at approximately 16 weeks, by

which time the entire respiratory tree, including terminal

bronchi-oles, has formed (Figure 30.2)

Alveoli

During the next phase, known as the canalicular stage (17–24

weeks), the respiratory parts of the lungs develop Canaliculi

(canals or tubes) branch out from the terminal bronchioles Each

forms an acinus comprising the terminal bronchiole, an alveolar

duct and a terminal sac (Figure 30.2) This is the primitive

alveolus.

The duct lumens become wider and the epithelial cells of some

of the primitive alveoli flatten to form type I alveolar cells (also

known as type I pneumocytes, or squamous alveolar cells) These

will be the cells of gaseous exchange

An invasion of capillaries into the mesenchyme surrounding the

primitive alveoli brings blood vessels to the type I alveolar cells

Towards the end of the canalicular stage some primitive alveoli

are sufficiently developed and vascularised to allow gaseous

exchange, and a foetus born at this stage may survive with

inten-sive care support

The saccular stage (or terminal sac period, from 25 weeks to

birth), describes the continued development of the respiratory

parts of the lungs Type II alveolar cells (also known as type II

pneumocytes, great alveolar cells or septal cells) begin to produce

surfactant, a phospholipoprotein that reduces the surface tension

of the fluid in the lungs and will prevent collapse of the alveoli

upon expiration and improve lung compliance after birth

During this stage many more primitive alveolar sacs develop

from the terminal bronchioles and alveolar ducts The blood–air

barrier between the epithelial type I alveolar cells and endothelial

cells of the capillaries develops in earnest, and the surface area

available to gaseous exchange begins to increase considerably

The final alveolar stage (36 weeks onwards) begins a few weeks

before birth and continues postnatally through childhood Alveoli increase in number and diameter enlarging the surface area avail-able to gas exchange (Figure 30.2) The squamous (type I alveolar) epithelial cells lining the primitive alveoli continue to thin before

birth, forming mature alveoli (Figure 30.3) Septation divides the

alveoli Surfactant is produced in sufficient quantities for normal lung function with birth Continued development through child-hood will increase the number of alveoli from 20–50 million at birth to around 400 million in the adult lung (Table 30.1)

Circulation

Two classes of blood circulation are present in the lungs: nary and bronchial Pulmonary arteries derive from the artery of the sixth pharyngeal arch and accompany the bronchial tree as it branches, while the pulmonary veins lie more peripherally This part of the circulatory system is involved in gaseous exchange, and until birth little blood flows through the pulmonary vessels For the changes to this circulatory system that occur at birth see Chapter 29

pulmo-Bronchial vessels supply the tissues of the lung These vessels are initially direct branches from the paired dorsal aortae

Clinical relevance

Respiratory distress syndrome (hyaline membrane disease) caused

by a lack of surfactant results in atelectasis (lung collapse) This affects premature infants, and treatment options include a dose of steroids given to the infant to stimulate surfactant production, or surfactant therapy Surfactant is administered to the infant directly down a tracheal tube These treatments together with oxygen therapy and the application of a continuous positive airway pres-sure using a mechanical ventilator mean that the prognosis is good

in many cases

Oesophageal atresia and tracheoeosphageal fistulas are relatively

common abnormalities If the separation of the trachea from the foregut is incomplete various types of communicating passages may persist This type of abnormality is often associated with other faults, including cardiac defects, limb defects and anal atresia It is also possible that an oesophageal atresia will lead to polyhydramnios as the amniotic fluid is not swallowed by the foetus, or pneumonia after birth as fluid may enter the trachea through the fistula Surgery is generally required

Ectopic lung lobes and abnormalities in the branching of the bronchial tree rarely produce symptoms

Congenital cysts of the lung can result in common infection sites and difficulty in breathing

Embryonic 3–5 weeks Initial bud and

branchingPseudoglandular 6–16 weeks Complete branchingCanalicular 17–24 weeks Terminal bronchiolesSaccular 25 weeks to term Terminal sacs and

capillaries cone into close contactAlveolar 8 months to childhood Well-developed

blood–air barrier

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Fig 31.1

Divisions of the gut tube, including the

cranial and caudal membranes, and the

retained connection to the yolk sac

through the vitelline duct (week 4)

Fig 31.4

Rotation and herniation of the small intestine

Fig 31.5

The urorectal septum splits the cloaca of the

hindgut into anterior urogenital and posterior

anorectal spaces during weeks 4 to 7

Fig 31.6Sagittal view of the mesenteries of the gut (a) The adult arrangement of mesenteries,highlighting greater and lesser omenta (b) The blood vessels of the gastrointestinal tractreach their targets within the mesenteries

Fig 31.2Blood supply to the divisions of the gut tube are direct branches from the aorta

Fig 31.3Rotation and growth of the stomach, along its horizontalaxis (weeks 4 to 6)

AortaCeliac trunkSuperiormesentericarteryInferiormesentericarteryBifurcation

of aorta intoiliac arteries

39 days

90 degrees clockwise rotation occurs

Navelopening

Digestive system: gastrointestinal tract Systems development 71

Time period: days 21–50

Induction of the tube

The gut tube forms when the yolk sac is pulled into the embryo

and pinched off (see Figure 18.2) as the flat germ layers of the early

embryo fold laterally and cephalocaudally (head to tail) Conse­

quently, it has an endodermal lining throughout with a minor

exception towards the caudal end Epithelium forms from the

endoderm layer and other structures are derived from the

mesoderm

Initially, the tube is closed at both ends, although the middle

remains in contact with the yolk sac through the vitelline duct (or

stalk) even as the yolk sac shrinks (Figure 31.1)

The cranial end will become the mouth and is sealed by the

buc-copharyngeal membrane, which will break in the fourth week,

opening the gut tube to the amniotic cavity The caudal end will

become the anus and is sealed by the cloacal membrane, which will

break during the seventh week

Buds develop along the length of the tube that will form a vari­

ety of gastrointestinal and respiratory structures (see Chapter 32)

Divisions of the gut tube

The gut is divided into foregut, midgut and hindgut sections by

the region of the gut tube that remains linked to the yolk sac and

by the anterior branches from the aorta that supply blood to each

part (Figure 31.2)

The foregut will develop into the pharynx, oesophagus, stomach

and the first two parts of the duodenum to the major duodenal

papilla, at which the common bile duct and pancreatic duct enter

The midgut includes the remainder of the duodenum and the small

and large intestine through to the proximal two­thirds of the trans­

verse colon The hindgut includes the distal third of the transverse

colon and the large intestine through to the upper part of the anal

canal

Blood supply

Each division of the gut is supplied by a different artery The

foregut is supplied by branches from the coeliac artery directly

from the descending aorta The midgut receives blood from the

superior mesenteric artery and the hindgut from the inferior

mesenteric artery (Figure 31.2).

Lower foregut

The foregut grows in length with the embryo, and epithelial cells

proliferate to fill the lumen The tube is later recanalised and only

becomes a squamous epithelium during the foetal period Failure

of this normal process causes problems of stenosis (narrowing) or

atresia (blocked) in the oesophagus or duodenum

Part of the foregut tube begins to dilate in week 4, the dorsal

side growing faster than the ventral side until week 6 This will

become the stomach, and the dorsal side becomes the greater

curvature The dorsal mesentery (dorsal mesogastrium) will

expand significantly to form the greater omentum

The stomach rotates to bring the left side around to become the

ventral surface, explaining why the left vagus nerve innervates the

anterior of the stomach (Figure 31.3) This rotation also moves

the duodenum into the adult C­shaped position

Twists of the midgut

The midgut also lengthens considerably, looping and twisting as

it does so, filling the abdominal cavity At approximately 6 weeks

the midgut grows so quickly there is not enough room in the abdomen to contain it, and it herniates into the umbilical cord (Figure 31.4)

The midgut also rotates through 270° counterclockwise (if you

were to be looking at the abdomen), bringing the developing caecum from the inferior abdomen up the left of the developing small intestine to the top of the abdomen, and around to descend

to its adult location in the lower right quadrant The axis of this rotation is the superior mesenteric artery and the rotation is of particular significance when considering the layout of the small and large intestines and accessory organs in adult anatomy.The midgut re­enters the abdomen in week 10, and it is thought that growth of the abdomen together with regression of the mes­onephric kidney and a reduced rate of liver growth are important factors in this occurring normally

Story of the hindgut and the cloaca

The last part of the gut tube, the hindgut, ends initially in a simple cavity called the cloaca The cloaca is also continuous with the allantois, a remnant of the yolk sac that largely regresses but con­tributes to the superior parts of the bladder in the human embryo

A wedge of mesoderm, the urorectal septum, moves caudally

towards the cloacal membrane as the embryo grows and folds during weeks 4–7 (Figure 31.5) The urorectal septum divides the

cloaca into a primitive urogenital sinus anteriorly and an anorectal canal posteriorly The urogenital sinus will form parts of the

bladder and the urogenital tract

The cloacal membrane ruptures in the seventh week, opening the gut tube to the amniotic cavity The caudal part of the lining

of the anal canal is thus derived from ectoderm and the cephalic part from endoderm Subsequently, the caudal part of the anal canal receives blood from branches of the internal iliac arteries and the cephalic part receives blood from the artery of the hindgut, the inferior mesenteric artery Similarly, portosystemic anastomoses also occur here

Mesenteries

Mesenteries of the gut form as a covering of mesenchyme passing over the gut tube from the posterior body wall of the embryo when the tube is in close contact with it With growth the gut tube moves further into the abdominal cavity and away from the posterior wall A bridging connective tissue forms suspending the gut and its associated organs within the abdomen in a dorsal mesentery for most of its length and a ventral mesentery around the lower foregut region The ventral mesentery is derived from the septum transversum

The dorsal mesentery will form the mesenteries of the small and large intestines of the adult gastrointestinal tract, and also forms

the greater omentum (Figure 31.6) The ventral mesentery will form the lesser omentum between the stomach and the liver, and the

falciform ligament between the liver and the anterior abdominal wall

The extensive lengthening and rotation of the midgut causes the dorsal mesentery to become considerably larger and more convoluted, and its initial simplicity explains the short diagonal attachment of the mesentery of the small intestine to the posterior abdominal wall in the adult When the hindgut finds its final posi­tion in the foetus the mesenteries of the ascending and descending colon fuse with the peritoneum of the posterior body wall

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 32.1

Organs begin to develop as buds from the gut tube

in the fourth week of development

Figure 32.3

Rotation of the intestine pulls the greater sac and the spleen

into position into the left of the abdomen, transverse section

Figure 32.4Early buds of the foregut Note the buds of the pancreas

on either side of the gut tube

Figure 32.5Rotation of the gut tube brings the ventral pancreatic budclose to the dorsal pancreatic bud

Figure 32.2The location of the developing spleen in the folds of the dorsal mesogastrium,with relation to the stomach and liver, transverse section

PancreasKidney

Lienorenal

GastrosplenicligamentStomachLiver

Dorsal pancreas

Lesser sacLung bud

Liver bud

Allantois

Cloaca

OesophagusStomachDorsal pancreaticbud

Left kidneyAortaSplenorenalligamentGastrosplenicligamentStomachHepatic

artery

Bileduct

Portalvein

Ventral bud

Liver

Gallbladder

Dorsal budSpleen

Digestive system: associated organs Systems development 73

Time period: day 21 to birth

Introduction

In Chapter 31 we looked at the development of the gastrointestinal

tract as a tube and mentioned a number of buds that sprout from

the tube and its associated mesenchyme These develop into a

number of organs (Figure 32.1)

Lung bud

As the oesophagus develops and elongates during week 4 the

res-piratory diverticulum buds off from its ventral wall (Figure 32.1)

To create two separate tubes a septum forms between the

respira-tory bud and the oesophagus called the tracheoesophageal septum

(see Figure 30.1) This creates the oesophagus dorsally and the

respiratory primordium ventrally (see Chapter 30)

Spleen

In the fifth week the spleen starts to develop from a condensation

of mesenchymal cells between the folds of the dorsal mesogastrium

(Figure 32.2) With the rotation of the stomach and duodenum the

spleen is moved to the left side of the abdomen, explaining the

adult location of the splenic artery, a branch of the coeliac trunk

The gastrosplenic ligament between the stomach and spleen is an

adult remnant of the dorsal mesogastrium, as is the splenorenal

ligament between the spleen and left kidney (Figure 32.3).

The spleen begins to create red and white blood cells in the

second trimester and is an important site of haematopoesis

during the foetal period After birth it stops producing red blood

cells and concentrates on its adult functions of the lymphatic and

immune systems, and of removing old red blood cells from

circulation

Liver and gallbladder

Beginning as an epithelial outgrowth from the ventral wall of the

distal end of the foregut the liver bud, or hepatic diverticulum

(Figure 32.1), appears at the end of week 3 Growing rapidly

during week 4 the liver bud grows into the septum transversum, a

sheet of mesodermal cells located between the pericardial cavity

and the yolk sac stalk The septum transversum will contribute to

the diaphragm (see Chapter 17) and the ventral mesentery here

Both the liver bud and septum transversum integrate to form parts

of the liver The liver bud grows within the ventral mesentery, and

retains a connection with the foregut that will become the bile duct

A cranial part of the liver bud will form the liver, and a caudal

bud will form the gallbladder (Figure 32.4).

The liver is formed from cells of different sources The liver bud from the foregut will form hepatocytes and the epithelial lining of the bile duct The vitelline and umbilical veins will form hepatic sinusoids Cells of the septum transversum will form the stroma and capsule (connective tissues) of the liver and also haematopoi-etic cells, Kupffer cells, smooth muscle and connective tissue of the biliary tract The lesser omentum between the stomach and the liver, and the falciform ligament between the liver and the anterior abdominal wall are the adult structures of the ventral mesentery

By week 10 of development the liver accounts for around 10%

of the embryonic weight At birth this reduces to 5% of total body weight A main embryological function of the liver is haematopoi-esis, with the liver producing red and white blood cells

With the rotation of the stomach and duodenum the route

of the common bile duct to the duodenum is altered from anterior

to the foregut to a posterior course (Figure 32.5), and is joined by

the pancreatic duct at the ampulla of Vater Eventually the bile

duct passes behind the duodenum and bile is formed by the liver

in week 12

Pancreas

Two pancreatic buds develop from the foregut (duodenum) giving dorsal and ventral buds (in the fourth and fifth week, respectively) within the mesentery The dorsal bud is larger, and the ventral bud

is a bud from the hepatic diverticulum (Figure 32.4)

With the rotation of the duodenum to the right the ventral bud moves dorsally (much like the movement of the bile duct entrance

to the duodenum) to rest below and behind the dorsal bud (Figure 32.5) In week 7 the duct systems of the buds fuse and the adult main pancreatic duct forms from the main duct of the ventral bud and the distal part from the dorsal bud Occasionally, the proximal part of the duct of the dorsal bud persists as an accessory duct that opens into the duodenum a little proximal to the main duct.The uncinate process and most of the head of the pancreas forms from the ventral bud, and the rest forms from the dorsal bud Exocrine and endocrine cells are all derived from endoderm,

taking separate differentiation pathways The islets of Langerhans

(endocrine cells) form in the third month and insulin is secreted from the fourth to fifth month

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Vitelline ligament(remnant of yolk sac)

Meckel’s orileal diverticulum

Loop of ileum

BladderUrethraLarge intestine

Rectourethralfistula Hind gut has failed

to open at anal pit

BladderUterusLarge intestine

Urethra VaginaRectumFistula

Maxillary process

Figure 33.1

The parts of the embryo that need to meet to form

the lip normally 30 day embryo

Figure 33.2Unilateral complete cleft lip Figure 33.3Isolated cleft palate

You can see the nasalcavity through this gapNasal prominence – lateral

Nasal prominence – medial

Digestive system: congenital anomalies Systems development 75

Time period: birth

Facial abnormalities

A relatively common congenital abnormality is cleft lip and/or

cleft palate which affects around 1 in 600–700 live births and has

a collection of defects

Cleft lip (cheiloschisis) can be incomplete (affects upper lip only)

or complete (continues into the nose) and unilateral (Figure 33.1)

or bilateral It is caused by the incomplete fusion of the medial

nasal prominence with the maxillary process (Figure 33.2) When

these fuse normally they form the intermaxillary segment, which

goes on to become the primary (soft) palate

The secondary (hard) palate forms from outgrowths of the

max-illary process called the palatine shelves Failure of these shelves

to fuse or ascend to a horizontal position causes cleft palate

(pala-toschisis) In very severe cases the cleft can continue into the upper

jaw Cleft palate is often accompanied by cleft lip (complete), but

not always (incomplete; Figure 33.3), and can also be unilateral or

bilateral

A cleft lip is generally diagnosed at the 20-week anomaly scan,

whereas cleft palates are diagnosed after birth Cleft lips require

surgical intervention before 3 months, whereas cleft palate surgery

should happen before the child reaches 12 months old Cleft lip

and palate can affect feeding and speech, but also hearing To aid

prevention of cleft lip and palate maternal dietary folic acid is

recommended (see also spina bifida, Chapter 15)

Foregut abnormalities

Abnormalities in development of the foregut can include stenosis

and atresia at various points along its length, and hypertrophy of

the pylorus of the stomach Depending upon the point of

restric-tion projectile vomiting can be a symptom, and the presence or

absence of bile in the vomit can help diagnose the location

The respiratory tract forms as a bud from the foregut, so

a tracheoesophageal fistula can form (Figure 33.4) The most

common variant sees the proximal oesophagus end blindly and the

trachea connected to the distal oesophagus There are many other

variations and frothy oral secretions are often a symptom Surgery

is required

A congenital hiatal hernia is caused by the oesophagus not

lengthening fully, preventing the diaphragm from forming

nor-mally and pulling the top of the stomach up into the thorax This

can affect the development of respiratory structures, and occurs in

varying severity

Midgut abnormalities

A remnant of the vitelline duct that connected the yolk sac to the

midgut may persist as an ileal diverticulum (also known as

Meck-el’s diverticulum; Figure 33.5) or as a vitelline cyst (also known as

an omphalomesenteric duct cyst) in the distal ileum An ileal

diver-ticulum is present in around 2% of the population, but the majority

are asymptomatic Ulceration may form here with bleeding If the

vitelline duct persists as fibrous cords between the abdominal wall

and the ileum loops of intestine may become twisted around it

The duct may survive as a true duct between the ileum and the

external umbilicus

The midgut may fail to complete its rotation or to fail to rotate

in the normal direction during development, giving abnormal tion or reverse rotation of intestine Abnormal rotation is caused

rota-by only a 90° rotation and gives a left-sided colon, whereas reverse rotation causes the transverse colon to lie posterior to the superior mesenteric artery after a 90° clockwise rotation of the midgut instead of the normal 270° counterclockwise rotation

Omphalocoele (or exomphalos) is the herniation of abdominal

contents into the umbilicus, and the contents remain covered by peritoneum and amnion (Figure 33.6) This can normally be diag-nosed by antenatal ultrasound scanning Omphalocoele is thought

to occur as a failure of the midgut to reenter the abdominal cavity after the normal herniation of weeks 6–10 Omphalocoele is often associated with cardiac and neural tube defects, trisomy 13 and 18 and Beckwith–Wiedemann syndrome

Associated organs

Liver Jaundice affects 60% of healthy newborn infants and has multiple

causes, often categorised by age of onset It is normally identified through the infant’s skin colour and bilirubin levels Most cases

of jaundice do not need treatment, but phototherapy helps reduce bilirubin levels In extreme cases an exchange transfusion is necessary

Pancreas

Due to abnormalities in the rotation of the ventral bud pancreatic tissue can end up surrounding the duodenum This is called an

annular pancreas It is possible that this tissue can constrict the

duodenum and cause a complete blockage Early signs can include

polyhydramnios It is normally treated with surgery.

Spleen

Splenic lobulation and an accessory spleen are relatively common

Rarer conditions include a wandering spleen and polysplenia

(mul-tiple accessory spleens)

Splenogonadal fusion, a very rare developmental anomaly,

results from the abnormal fusion of the splenic and gonadal mordia during prenatal development

pri-Hyposplenism (reduced splenic function) may occur because of

a congenital failure of the spleen to form Affected individuals are

at increased risk of bacterial sepsis

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 34.2The mesonephric forms functional nephrons, but all degenerate

in the 3rd month The mesonephric duct and tubules of themesonephros form parts of the male reproductive system

Figure 34.1

The mesonephros forms as the pronephros

degenerates in week 4

Figure 34.4

The definitive kidney forms from the

ureteric bud and the metanephric cap

Figure 34.7

The collecting system of the adult

kidney forms from the ureteric bud Figure 34.6The development of a nephron in the

metanephros

Figure 34.8

A male bladder, ureters, urethra and prostate gland

Figure 34.5The ureteric bud branches, and the metanephricblastema caps these branches The ureteric budwill form the urine collecting system, and the metanephric cap will form the nephrons, along with capillaries from the aorta

Figure 34.3The metanephros begins as theureteric bud in week 5

Mesonephric duct

PronephrosMesonephros

Nephrogenic cordCloaca

Metanephriccap

Gut tubeMetanephros

SomiteMesonephrenicductMesonephrosGonadal ridge

Major calyx

Uretericbud

Metanephric capUreteric bud(branch)

Bowman’s capsule(forming)

Bowman’s capsule(forming)

Capillary

Collecting ductCollecting tubule

GlomerulusUreter

Ureters enterthe bladderProstate glandBladder

Urethra

Renal pelvis

UreterCalyces

Time period: day 21 to birth

Introduction

The development of the urinary system is closely linked with that

of the reproductive system They both develop from the

intermedi-ate mesoderm, which extends on either side of the aorta and forms

a condensation of cells in the abdomen called the urogenital ridge

The ridge has two parts: the nephrogenic cord and the gonadal ridge

Urinary system Systems development 77

The pronephros appears in the third week in the neck region of

the embryo and disappears a week later In humans this is a

primi-tive, non-functional kidney that consists of vestigial nephrons

joined to an unbranched nephric duct

Mesonephros

Appearing in the fourth week the first functional kidney unit, the

mesonephros, forms as the pronephros begins to regress (Figures

34.1 and 34.2) The mesonephric ducts (Wolffian ducts) are

epithe-lia-lined tubes that form in the intermediate mesoderm and extend

caudally to the cloaca They stimulate formation of the

mesone-phros itself as mesonephric tubules (different to the ducts) from the

mesenchyme The tissue of the mesonephros appears initially as a

segmented structure along the mesonephric duct

Renal corpuscles develop from mesonephric tubules (Bowman’s

capsule) and capillaries from the dorsal aortae (glomerulus) At the

lateral end the tubules join the mesonephric duct The duct

dis-charges into the cloaca where the bladder will form The

mesone-phros starts to produce urine at about 6 weeks but degenerates

almost completely between weeks 7 and 10

The mesonephric ducts contribute to the ducts of the male

reproductive system, but regress in the female foetus (see

Chap-ter 36)

Metanephros

The third renal structure that develops will finally become the

adult kidney It starts to appear at the beginning of the fifth week

as a bud from the caudal end of the mesonephric duct, called the

ureteric bud (Figures 34.3 and 34.4).

The bud branches and develops into the collecting parts of the

adult kidney: the ureter, renal pelvis, calyses and collecting tubules

The bud grows into surrounding intermediate mesoderm and

induces the cells in that region (the metanephric blastema) to form

a metanephric cap upon the ureteric bud.

As the ureteric bud forms collecting tubules, cells of the

metane-phric cap form nephrons that link to the collecting tubules

Recip-rocal interactions between the buds and the caps initiate and

maintain this development (Figure 34.5)

Capillaries grow into the Bowman’s capsule from the dorsal

aortae and convolute to form the glomeruli (Figure 34.6) These

functional renal units produce urine from week 12 onwards

The formation of nephrons continues until birth when there are

approximately 1 million nephrons in each kidney Infant kidneys

are lobulated because of the branching of the calyces (Figure 34.7),

but further growth and elongation of the nephrons after birth

pushes out the kidney and the lobulation disappears

Blood supply

The location of the metanephros changes during development

from the level of the pelvis, through growth of the embryo and

migration of the kidneys, to the lumbar region They also rotate

medially in ascent As they ascend, a series of blood vessels from

either the common iliac arteries or aorta generate and degenerate

to continually supply the kidneys Usually, the most cranial remain and become the renal arteries

Bladder and urethra

In week 4 the cloaca is split into the ventral urogenital sinus and the dorsal anal canal by the urorectal septum (see Figure 31.5).

The urogenital sinus can be split into a further three parts The top part is the biggest and becomes the bladder, the middle part forms the urethra in the female pelvis and the prostatic and membranous urethra in the male (Figure 34.8), and the lowest part forms the penile urethra in the male and the vestibule in the female The allantois also contributes to the upper parts of the bladder

The mesonephric ducts become incorporated into the posterior wall of the bladder The openings of the mesonephric ducts and ureters enter the bladder separately Remember that the ureters form from the metanephric ducts The ureters move anteriorly whereas the mesonephric ducts move posteriorly and become the ejaculatory ducts in the male pelvis

The specialised transitional epithelium of the bladder develops

from the endoderm of the urogenital sinus

The ventral surface of the cloaca (which becomes the urogenital sinus) is continuous with the allantois, which degenerates after

birth to form the urachus and eventually the median umbilical ment (an embryological remnant with no clinical significance) The

liga-medial umbilical ligaments are the remnants of the umbilical

arter-ies, which are a little lateral to the urachus

Clinical relevance

Incomplete division of the ureteric bud can lead to supernumerary kidneys and, more commonly, supernumerary ureters.

Kidney cysts form when the developing nephrons fail to connect

to a collecting tubule in development, or the collecting ducts fail

to develop There are dominant and recessive forms of polycystic kidneys The recessive form is more progressive and often results

in renal failure in childhood

Balance of fluid in the amnion is vital in the development of the embryo If urine is not being produced there is a reduction in the

amniotic fluid and oligohydramnios develops This can be a symptom of bilateral renal agenesis, in which both kidneys fail to

form This is lethal Unilateral renal agenesis generally causes no symptoms

Accessory renal arteries are quite common, especially on the left

and often are only seen during a surgical procedure as they are asymptomatic They enter the kidney at the superior and inferior poles Abnormal rotation or location of the kidneys may be found

in a patient, and they may fail to ascend into the abdomen The inferior poles of the left and right kidneys can fuse, forming a horseshoe kidney In this case the kidney cannot ascend as it gets snagged on the inferior mesenteric artery

Bladder defects may occur, such as exstrophy in which part of

the ventral bladder wall is present outside of the abdominal wall

A urachal cyst, fistula or sinus can form if the degeneration of the

allantois is not completed

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figuer 35.1

The mesonephric and paramesonephric ducts at the indifferent stage

Figure 35.3

During the development of the female

reproductive system the paramesonephric

ducts form the uterovaginal primordium,

and the mesonephric duct degenerates

Figure 35.6

The male reproductive ducts form from the

mesonephric duct The paramesonephric

duct has degenerated

Figure 35.7

The ducts of the adult male reproductive system Figure 35.8Development of female external genitalia Figure 35.9Development of male external genitalia

Figure 35.4Sinovaginal bulbs form where the uterovaginalprimordium meets the urogenital sinus Thevagina will form from both these structures

Figure 35.5The adult female reproductive system

SinovaginalbulbsUrogenitalsinus

Figure 35.2The mesonephric and paramesonephric ducts at the indifferent stage

SomiteMesonephric ductParamesonephricduct

Nephrogenic cordGonadal ridge

Mesonephric duct

Paramesonephricduct

GonadsMesonephros

Seminalvesicles

Mesonephric ductdegenerating

ClitorisUrethral openingVestibuleVaginal opening(hymen)Labia minoraLabia majora

Labia majoraUrethral groove

Primordial phallusLabioscrotal swellingsUrogenital membraneUrogenital foldsAnus

Indifferent stage (weeks 4–7)

Epithelial cord growinginwards to meet the urethraGlans

PenisUrethral grooveScrotumScrotal raphe

External urethralopeningMidline raphe

Primordial phallusLabioscrotal swellingsUrogenital membraneUrogenital foldsAnus

Cortical cords

Uterovaginal primordium

Reproductive system: ducts and genitalia Systems development 79

Time period: day 35 to postnatal

development

Introduction

The reproductive systems develop from a series of epithelial

cell-lined ducts, derived from mesoderm The initial stage of genital

development is the same for both sexes up to week 7, and is called

the indifferent stage.

Ducts

The indifferent stage involves the mesonephric ducts (or Wolffian

ducts) from the developing urinary system and the

paramesone-phric ducts (or Müllerian ducts), named because of their location

lateral to the mesonephric ducts (Figures 35.1 and 35.2) The

para-mesonephric ducts form from longitudinal invaginations of the

surface epithelium of the gondal ridge

Female

The paramesonephric ducts descend, meet in the midline and fuse

in the pelvic region to form the uterovaginal primordium (Figure

35.3) This bulges into the dorsal wall of the developing urogenital

sinus (see Chapters 31 and 34) but does not break the wall The

bulge forms the paramesonephric tubercle (or sinus tubercle, or

Müller tubercle)

The paramesonephric ducts open into the peritoneal cavity, and

the free unfused cranial ends become the uterine tubes The uterus

forms from the midline uterovaginal primordium

The paramesonephric tubercle induces the urogenital sinus to

form 2 outgrowths of cells within its lumen These outgrowths

proliferate and form the sinovaginal bulbs, which fuse and form the

vaginal plate (Figure 35.4) This will canalise to form a hollow core,

which is completed by the fifth month

The inferior part of the vagina probably forms from the vaginal

plate, and the superior part from uterovaginal primordium The

vagina is separated from the urogenital sinus by the hymen

The female reproductive system (Figure 35.5) is likely to grow

from 2 tissue origins: the lining of the lower portion of the vagina

is endodermal and the upper portion, fornices and uterus are

mesodermal The muscle and connective tissues of the vagina and

uterus are derived from the surrounding mesenchyme

The mesonephric ducts degenerate, although remnants may

remain

Male

Mesonephric ducts become the efferent ductules and epididymis of

the testes, the ductus deferens (or vas deferens) and the ejaculatory

duct (Figures 35.6 and 35.7)

The seminal vesicles form as an outgrowth from the ductus

deferens, whereas the prostate gland arises from numerous

out-growths from the urethra The endodermal cells of the urethra

differentiate to become the glandular tissue of the prostate gland,

and the surrounding mesenchyme forms the smooth muscle and

connective tissue

Paramesonephric ducts degenerate (although remnants can

remain)

External genitalia

Until the ninth week of development the external genitals appear

the same for both sexes (Figures 35.8 and 35.9) You cannot see

the difference in the sex of a developing embryo until around 11

weeks’ gestation To prevent mistakes made in ultrasound fication, if the sex of the foetus is required it is identified at the 20-week scan

identi-During the indifferent stage, the cloacal membrane is surrounded

by mesenchymal folds called urogenital (cloacal) folds that fuse ventrally into a genital tubercle Around week 7, the urogenital septum splits the cloacal membrane into a ventral urogenital mem- brane and a dorsal anal membrane.

Another pair of folds develop lateral to the urogenital folds,

called the labioscrotal swellings The urogenital membrane

degen-erates leaving the urogenital sinus in direct communication with the amniotic cavity The genital tubercle elongates and forms the

primordial phallus.

Female Induced by oestrogens secreted from the placenta and foetal ovaries, the genital turbercle develops into the clitoris (Figure

35.8) During the third and fourth months the clitoris is larger than its male counterpart The urogenital groove remains open and

develops into the vestibule which contains the openings of the

vagina and urethra The urogenital folds remain largely unfused

(the two sides only meet posteriorly) and become the labia minora The labioscrotal swellings become the labia majora.

Male

Induced by androgens secreted from the developing testes, the

primordial phallus grows to form the penis (Figure 35.9) The

urogenital sinus forms a groove bound laterally by the urogenital folds, and endodermal cells divide and line the groove which is

now termed the urethral plate The urethral folds eventually fuse

on the underside (penile raphe) surrounding a tube (the spongy part of the urethra)

The urethra temporarily ends blindly in the anterior part of the penis In the fourth month the terminal part of the urethra is formed when cells from the glans grow internally producing an epithelial cord A lumen then forms and creates the external ure-

thral meatus The lateral genital swellings form the scrotum and

the visible line of fusion is the scrotal raphe

Sex determination

The SRY gene (sex-determining region of the Y chromosome) encodes for a transcription factor that is expressed in the gonad during the indifferent stage, triggering male development If this transcription factor is absent female development occurs

Clinical relevance

Hypospadias is caused by incomplete fusion of the urethral folds

in the male, and the urethra opens onto the ventral surface of the

penis Epispadias results from the genital tubercle developing in

the area of the urorectal septum, causing the urethra to open on the dorsal surface of the penis Epispadias usually occurs in males but can occur in females and results in a split clitoris and an abnormally positioned urethral opening

Congenital adrenal hyperplasia is an enzyme deficiency causing

the adrenal glands to fail to produce sufficient cortisol and terone, but the body produces excess androgens This can result in ambiguous genitalia development in females but will not affect males Further developmental problems occur, such as precocious puberty

aldos-Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Gut tubeGonadal ridgePrimitive sex cordsGerm cells

Cortical cords

Female

Germ cellsCortexMedullaGut

Foregut

Midgut

Hindgut

NephrogeniccordGonadalridgeMigratinggerm cells

Figure 36.5Route of the testes’ descent (a) Possible ectopic locations and (b) the normal descent

Medullary cords

Male

Medulla

Germ cellsCortex

Abdominallocation runs down toscrotal location

SuperficialectopicPrepenileFemoralTransversescrotalPerineal

(a) (b)

Epididymis(mesonephric duct)Rete testis

Figure 36.1

Migration of cells from the yolk sac to the

gonadal ridge Figure 36.2Migration of cells from the yolk sac to the gonadal ridge

Transverse section, week 5

Note the formation of the primitive sex cords

Figure 36.3

Female gonadal development

at about 12 weeks

Figure 36.4Male gonadal development

at about 12 weeks

Lung budLiver budAllantoisCloaca

OesophagusDorsal pancreaticbud

Mesonephric ductParamesonephricduct

Reproductive system: gonads Systems development 81

Time period: day 30 to postnatal

development

Introduction

In the chapter on renal development (see Chapter 34) we talked

about the development of the gonadal ridge from intermediate

mesoderm, an important source of cells for the reproductive system

and the location for the beginning of the development of the

gonads

Gonads

Gonads are formed from three sources of cells: the intermediate

mesoderm, the mesodermal epithelium that lines the developing

urogenital ridge and germ cells.

Germ cells originate in the extra-embryonic endoderm of the

yolk sac near the allantois and migrate along the dorsal mesentery

of the hindgut to reach the gonadal ridge at the beginning of week

5 (Figure 36.1) By the sixth week they invade the gonadal ridge

(see Figure 34.2) Also at this time the epithelium overlying the

mesoderm begins to proliferate, penetrating the mesoderm and

forming cords that are continuous with the surface epithelium

(Figure 36.2)

This indifferent gonad has a discernible external cortex and

internal medulla If the migrating germ cells fail to arrive the

gonads will not develop because of the absence of reciprocal

inter-actions between germ cells and surrounding epithelia

Female

In the early female gonad the cortex develops and the medulla

regresses The primitive sex cords dissociate and form irregular cell

clusters containing germ cells (Figure 36.3) These cords and

clus-ters disappear and are replaced with blood vessels and connective

tissue

Surface epithelia continue to proliferate and produce a second

wave of sex cords that remain close to the surface In the fourth

month of development these also dissociate and form cell clusters

surrounding one or more germ cells This is the primitive follicle

and the surrounding epithelial cells develop into follicular cells (see

Figure 8.1) Each primitive germ cell becomes an oogonium

Oogonia divide significantly before birth but there is no division

postnatally

A part of peritoneum attached to the gonad develops into the

gubernaculum This structure passes through the abdominal wall

(the future inguinal canal) and attaches to the internal surface of

the labioscrotal swellings (see Figure 35.8) The ovaries descend

into the pelvis, and the gubernaculum becomes attached to the

uterus In the adult the gubernaculum remains as the round

liga-ment (passing through the inguinal canal) of the uterus and the

ovarian ligament.

Male

The cortex regresses and the medulla develops (Figure 36.4)

Testes develop quicker than ovaries, and the primitive sex cords

do not degenerate but continue to grow into the medulla

Testosterone producing cells, called Leydig cells, develop from

mesoderm of the gonadal ridge and are located between the

devel-oping sex cords They produce testosterone by week 8

The primitive sex cords break up and form two networks of

tubes: the rete testis and the seminiferous tubules The tunica inea (thick fibrous connective tissue) develops to separate the net-

albug-works from the surface epithelia The rete testes are the connection between the seminiferous tubules and the efferent ducts of the

testes (see Figure 7.1), which are derived from the mesonephric tubules (see Chapter 34).

In the fourth month the seminiferous tubules contain two important cell types: primitive germ cells that form spermatogo-

nia, and Sertoli cells that have support roles for the cells passing through spermatogenesis The male gubernaculum runs from the

inferior pole of the testis to the labioscrotal folds (see Figure 35.9) and guides the testis into the scrotum, along with the ductus defer-ens and its blood vessels, as the foetus becomes longer and the pelvis becomes larger The inguinal canal normally closes behind the testis, but failure of this process increases the risk of an indirect inguinal hernia

Clinical relevance

Undescended testes (cryptorchidism) describes the failure of the

testes to descend normally into the scrotum by birth This may occur bilaterally or unilaterally, and is more common in premature males The testes may remain in the abdominal cavity, at a point along their normal route of descent or within the inguinal canal (Figure 36.5) Often, the testes will have descended to the scrotum

by the end of the first year, but testes that remain undescended are likely to cause fertility problems Undescended testes, even if they later descend, are linked to an increased risk of testicular cancer

Hormonal imbalances can result in a varied range of mental abnormalities to the reproductive system Chromosomal defects are also responsible for many genital abnormalities, often

develop-presenting with other congenital defects Those with gonadal genesis have male chromosomes but no testes Patients can have

dys-female external genitalia and underdeveloped dys-female internal talia or ambiguous external genitalia and a mixture of both sexes internally, but are often raised as girls

geni-Ovarian and testicular cancers are relatively common forms of cancer If testicular cancer is suspected it is often from a lump

found in one testis and diagnosed through an ultrasound scan It

is important to remember that lymph drainage is to the toneal para-aortic lymph nodes rather than pelvic nodes, and these are involved in the staging of testicular cancer Affected nodes must also be removed surgically together with the testis The prog-

retroperi-nosis for testicular cancers is generally good Ovarian cancer

symp-toms are often absent and if present, unspecific An increase in abdominal size and urinary problems are possible Surgical treat-ment is often required but because of the lack of early symptoms and diagnosis the prognosis is generally poor

Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Posterior lobe

of the pituitary gland

Sphenoidbone

Tongue

Brain

Secondarypalate

Adult

SphenoidbonePituitaryglandHypothalamus

Sympatheticganglia(developing)

Foetal cortex

of thesuprarenalgland

GI tract

Abdominalmesenchyme

after birth

Kidney

Kidney

Permanent cortex differentiates

to form the layers of zona glomerulosa, zona fasciculataand zona reticularisVertebrae

Kidney

Mesenchymal cellssurround the foetalcortex and form thepermanent cortex

Neural crest cellspenetratesuprarenal cortexand form thesuprarenal gland’s medulla

Week 8

Neural crest cellsmigrate to suprarenal cortex from sympathetic ganglion

Time period: day 24 to birth

Introduction

The glands of the endocrine system begin to form during the

embryonic period and continue to mature during the foetal period

Functional development can be detected by the presence of the various hormones in the foetal blood, generally in the second tri-mester of pregnancy

The development of the gonads, pancreas, kidneys and placenta are covered elsewhere in this book

Endocrine system Systems development 83

Pituitary gland

Also known as the hypophysis, the pituitary gland develops from

two sources An outpocketing of oral ectoderm appears in week 3

in front of the buccopharyngeal membrane (Figure 37.1) This

forms the hypophysial diverticulum (or Rathke’s pouch), which will

become the anterior lobe

The second source is an extension of neuroectoderm from

the diencephalon, called the neurohypophysial diverticulum (or

infundibulum) The infundibulum grows downwards, developing

into the posterior lobe These two parts grow towards one another

and by the second month the hypophysial diverticulum is isolated

from its ectodermal origin and lies close to the infundibulum

Growth hormone secreted by the pituitary gland can be detected

from 10 weeks

Hypothalamus

The hypothalamus begins to form in the walls of the diencephalon

(see Chapter 42), with nuclei developing here that will be involved

in endocrine activities and homeostasis

Pineal body

The pineal body first appears as a diverticulum in the caudal part

of the roof of the diencephalon It becomes a solid organ as the

cells here proliferate

Adrenal glands

The adrenal (or suprarenal) glands develop from two cell types

The cells of the cortex differentiate from mesoderm of the

poste-rior abdominal wall near the site of the developing gonad (Figure

37.2) The adrenaline and noradrenaline secreting cells of the

medulla are derived from migrating neural crest cells that formed

a sympathetic ganglion nearby These cells become surrounded by

the cell mass of the cortex

The foetal cortex produces a steroid precursor of oestrogen that

is converted to oestrogen by the placenta More mesenchymal cells

surround the foetal cortex and will become the layers of the

per-manent cortex

The adrenal glands are exceptionally large in the foetus because

of the size of the cortex which regresses after birth Substances

secreted from the adrenal glands are involved in the maturation of

other systems of the embryo, such as the lungs and reproductive

organs

Thyroid gland

This is the first endocrine gland to develop, beginning at about 24

days between the first and second pharyngeal pouches from a

proliferation of endodermal cells of the gut tube It begins as a

hollow thickening of the midline where the future tongue will

develop It eventually becomes solid and then splits into its two

lobes

As the thyroid descends into the neck it remains connected to

the tongue via the thyroglossal duct with an opening on the tongue

called the foramen cecum The duct degenerates between weeks 7

and 10 and the thyroid reaches its end location anterior to the

trachea by week 7 If parts of the duct remain the person may also

have a pyramidal lobe This is quite common and seen in about

The inferior parathyroid glands develop from epithelium

(endo-derm) of the dorsal wing of the third pharyngeal pouch The cells

here move with the migration of the thymus gland into the neck (see Chapter 40) When this connection breaks down they become located on the dorsal surface of the thyroid gland

Endoderm cells of the dorsal wing of the fourth pharyngeal arch

begin to collect and differentiate to form the superior parathyroid glands (initially the superior parathyroid glands are inferior to the inferior parathyroid glands) These cells are associated with the developing thyroid gland and migrate with it, but for a shorter distance than the cells of the inferior parathyroid glands (see Chapter 41) They also rest on the dorsal surface of the thyroid, but generally more medially and posteriorly

Clinical relevance

Pituitary gland Congenital hypopituitarism is a decrease in the amount of one or

more of the hormones secreted by the pituitary gland Symptoms are wide ranging, depending upon which hormones are affected The cause is often hypoplasia of the gland or complications with delivery Treatment is commonly oral or injection replacement of the insufficient hormones

Adrenal glands Congenital adrenal hyperplasia is an autosomal recessive disease

causing excessive production of steroids, with 95% of patients

deficient in the enzyme 21-hydroxylase (required in the production

of adrenal secretions) There are degrees of severity and this can cause ambiguous genitalia and infertility Various treatment options are available and can include glucocorticoids, sex hormone replacement and genital reconstructive surgery

Thyroid gland Congenital hypothyroidism is a deficiency in thyroid hormone pro-

duction Symptoms include excessive sleeping and poor feeding Newborn infants are screened for this and if this deficiency is found treatment is a daily thyroxine tablet

Ectopic thyroid tissue left behind during migration is relatively common but asymptomatic Parts of the thyroglossal duct may persist and form a midline, moveable cyst in a child

Parathyroid glands Hypoparathyroidism is an absence of parathyroid hormone Symp-

toms are wide ranging but often not diagnosed until 2 years of age They include seizures and poor growth Treatment includes vitamin D and calcium supplements

Ectopic parathyroid tissue left behind during migration is tively common but asymptomatic It is more common for the inferior parathyroid glands

rela-Embryology at a Glance, First Edition Samuel Webster and Rhiannon de Wreede

Figure 38.1

Lateral aspect of the 4 week embryo with the

pharyngeal arches visible lying cranial to the somites

Figure 38.4

The arches appear and develop at different rates, so the first

arches are more developed by the time the sixth arches appear

Each arch has its own nerve, artery, connective tissue cells

and muscle cells Figure 38.5Structures derived from the cells of the first pharyngeal arch

Figure 38.6

Week 6 The clefts between most of the pharyngeal arches have

disappeared, but the first cleft remains as the external acoustic

meatus The first pouch will form the pharyngotympanic tube

Figure 38.7External acoustic meatus(1st pharyngeal cleft)

Figure 38.2Ventral aspect of the cranial part of theembryo showing the structures developingaround the stomodeum, including thefirst, second and third pharyngeal arches

Figure 38.3

An outline of the relationship betweeneach pharyngeal arch and each pharyngealcleft and pouch

EN DODERM

EC TO DE RM

Pouch

Arch(mesenchyme)

Insideembryo

Outsideenvironment

Tensor tympanimuscle

Malleus andincus bones

Muscles of

(CN V2)

Mandibular nerve(CN V3)

Anterior belly ofdigastric muscleMylohyoid muscleMandibleMaxilla

Head

Tail

PharyngealarchesStomodeumSomites

Nerve

Stomodeum

Stomodeum

First archFirst cleftFirst pouch

Nasal placode

Maxillary prominence(first arch)Mandibular prominence(first arch)

Second archThird arch

Gut tube

EndodermConnective

tissue

Blood vessel

Muscle cells

Arch 1Arch 2Arch 3Arch 4Arch 6Gut tube